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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.85 no.4 Rio de Janeiro July/Aug. 2010
Carolina Balbi MosqueiraI; Laura de Albuquerque FurlaniII; Augusto Frederico de Paula XavierIII; Paulo Rowilson CunhaIV; Alda Maria Penna GalvãoV
IDermatology Resident of the Faculty of Medicine of Jundiaí - Jundiaí (SP), Brazil
IIDermatology Resident of the Faculty of Medicine of Jundiaí - Jundiaí (SP), Brazil
IIIDermatology Resident of the Faculty of Medicine of Jundiaí - Jundiaí (SP), Brazil
IVFull Professor of the Dermatology Service of the Faculty of Medicine of Jundiaí - Jundiaí (SP), Associate Professor of the Faculty of Medicine of Jundiaí - Jundiaí (SP), Brazil
VMedical doctor, specialist in Dermatology - Jundiaí (SP), Brazil
Acquired bullous epidermolysis is a chronic and rare bullous subepidermal disease. It usually begins in adulthood and its etiology is unknown although it is associated with antibodies against type VII collagen. There are spontaneous and trauma induced formation of blisters that may cause serious complications. Treatment is disappointing and difficult. Apart from conventional therapy with systemic corticosteroid, new therapeutic modalities such as intravenous immunoglobulin are currently being used. This report highlights the extremely difficult clinical management of this rare disease and the important improvement provided by intravenous immunoglobulin.
Keywords: Acquired bullous epidermolysis; Immunosuppressive agents; Immunoglobulins, intravenous
Acquired bullous epidermolysis (EBA) is a chronic and rare bullous subepidermal disease which develops on the skin and mucosas and that usually starts in adulthood.1,2 It has an incidence of 0,2 per million of people, regardless race or sex.3 There is association with allele HLA DR2, suggesting predisposition to EBA among carriers of this phenotype who are also more sensitive to bullous lupus.4 The etiology is unknown although it is associated with the presence of antibodies against type VII collagen, main structural component of the anchorage fibrils of the dermo-epidermic junction, that could lead to a decrease in the number of anchorage fibrils. 2 The skin is fragile, bullae are formed spontaneously or usually after traumas. Lesions occur in backing regions or areas predisposed to trauma and result in scar with or without whiteheads. 1,5 It can cause serious complications and can be associated with other systemic diseases.1 The histologic analysis of the lesion shows subepidermic bulla, with varied dermic inflammatory infiltrate1 The EBA is characterized with direct immunofluorescence, by the linear deposition of immunoreagents (deposits of IgG and C3) in the dermoepidermic junction.1,3 The indirect immunofluorescence of the patient serum can show the antibodies. In the salt-split skin technique autoantibodies can be found on the dermic side, after artificial cleavage.6
Treatment is frequently disappointing and difficult. 1,7,8 Recently, new promising therapeutical modalities have been reported such as cyclosporin, colchicine, plasmapheresis, extracorporal photochemotherapy and above all, intravenous immunoglobulin (IgIV).1,7,8
Female patient, aged 54, complained about the appearing of flaccid and tense bullae for six years, some of them hemorragic, others with clear content (Picture 1). Clinical examination found not only the mentioned bullae but also erosions on the oral and conjuctival micosas, associated with scars and whiteheads, without ungual onset (Pictures 2, 3 and 4).
Histopathologic exam showed subepidermic bulla and lymphocytery infiltrate on the superior dermis; direct immunofluorescence showed linear deposit of IgG, IgA and C3 in the basal membrana zone and indirect immunofluorescence( salt-split skin) revealed deposit of IgG in the dermic side of the bulla, confirming the diagnosis of EBA ( Picture 5).
The patient was treated with high doses of prednisone (100 mg/day), and thalidomide (100 mg/day). The disease developed new lesions, hoarseness, epistaxis and dysphagia apart from high blood pressure and diabetes as consequences of corticotherapy. Even with the introduction of methotrexate and dapsone, after four months the patient presented respiratory failure because of laryngeal stenosis being even necessary a tracheostomy (Picture 6). Due to the fact that it was a refractory case, it was decided to treat the patient with intravenous human immunoglobulin 400mg/Kg/day, for five consecutive days (six cycles every four weeks) with important clinical improvement.
The EBA, as it was shown in the reported case, is a potentially serious and limiting disease. Its conventional treatment is many times frustating, with modest clinical result, short remissions and many recidiations. The lesions frequently located on the hands and feet limit, a lot, the daily activities of patients.1
Conventional therapy presents modest clinical result and consists of using systemic corticosteroid in high doses, for long periods of time, in monotherapy or in combination with immunosupressive agents.7 The immunosupressive adjuvants, such as azathioprine, methotrexate, and cyclophosphamide, and the antiimflammatories like dapsone and thalidomide, are used not only because of their corticosteroid saving effect but also to try to induce remission in patients when the disease is refractory to treatment with corticosteroids singly. New therapeutics have been used in a limited number of cases: colchicine, cyclosporin, plasmapheresis, extracorporal photochemotherapy and IgIV.1
As the patient did not present a satisfactory response to conventional corticotherapy treatment combined with thalidomide, methotrexate and dapsone apart from the fact that the patient also presented important side effects, IgIV therapy was considered. According to preliminary studies IgIV can bring great benefit for the treatment of EBA.1,7-15
The reagent used in the IgIV therapy is a product prepared from serums obtained from 1000 to 15000 donors per lot.1,7,13 Immunoglobolin acts modulating the autoimune response, occurring reduction on the titer of antibodies, apart from its neutralization.12,13
The most frquent side effects associated with this therapy are fever, chills, rubor, headache, myalgias, nausea and tachycardia. Serious secundary effects such as haemolysis, transitory neutropenia, acute kidney failure, aseptic meningitis and anaphylaxis 8 may occur. The patient presented minor sialorrhoea.
The recommended dose of IgIV is 400mg/kg/day, for five days, totalizing 2g/kg per cycle, in slow infusion for approximately four hours. It is repeated a new cycle every four to six weeks. 1,7,8
After the therapy the patient presented stabilisation of the disease, with decrease in the number of lesions after minor traumas and improvement in the process. of healing.
Although the high cost of the treatment is a limiting factor, the IgIV proved to be a viable therapeutic option, efficient and with good tolerance by patients, bringing important improvements on the cutaneous fragility, decrease in lesions and improvement in the quality of life of patients and therefore should be considered, at the begining of the disease, before the appearance of complications generated by the treatment and by the disease itself.
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8. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol. 2003;139:1051-9. [ Links ]
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11. Mohr C, Sunderkötter C, Hildebrand A, Biel K, Rütter A, Rütter GH, et al. Successful treatment of epidermolysis bullosa acquisita using intravenous immunoglobulins. Br J Dermatol. 1995;132:824-6. [ Links ]
12. Harman KE, Black MM. High-dose intravenous immune globulin for the treatment of autoimmune blistering diseases: an evaluation of its use in 14 cases. Br J Dermatol. 1999;140:865-74. [ Links ]
13. Jolles S. High-dose intravenous immunoglobulin (hdIVIg) in the treatment of autoimmune blistering disorders. Clin Exp Immunol. 2002;129:385-9. [ Links ]
14. Kofler H, Wambacher-Gasser B, Topar G, Weinlich G, Schuler G, Hintner H, et al. Intravenous immunoglobulin treatment in therapy-resistant epidermolysis bullosa acquisita. J Am Acad Dermatol. 1997;36:331-5. [ Links ]
15. Harman KE, Whittam LR, Wakelin SH, Black MM. Severe, refractory epidermolysis bullosa acquisita complicated by an oesophageal stricture responding to intravenous immune globulin. Br J Dermatol. 1998;139:1126-7. [ Links ]
Mailing address: Received on 13.08.2008. * Study carried out in the Dermatology Service of the Faculty of Medicine of Jundiaí - Jundiaí (SP), Brazil.
Paulo Rowilson Cunha
Address: Isaí Leiner 152, Jardim Brasil
13201854 Jundiaí - SP, Brazil
Phone: +55 11 4521 8459
Approved by the Advisory Board and accepted for publication on 08.12.2008
Conflict of interest: None
Financial funding: None
Received on 13.08.2008.
* Study carried out in the Dermatology Service of the Faculty of Medicine of Jundiaí - Jundiaí (SP), Brazil.